US11389411B2 - Pharmaceutical composition, containing NM23 activator, for inhibiting cancer metastasis - Google Patents

Pharmaceutical composition, containing NM23 activator, for inhibiting cancer metastasis Download PDF

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US11389411B2
US11389411B2 US16/609,094 US201816609094A US11389411B2 US 11389411 B2 US11389411 B2 US 11389411B2 US 201816609094 A US201816609094 A US 201816609094A US 11389411 B2 US11389411 B2 US 11389411B2
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cancer
formula
compound
present disclosure
pharmaceutical composition
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US20200078319A1 (en
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Kong Joo Lee
Hee-Yoon Lee
Je Jin Lee
Eun-Kyoung SEO
Eun Sun LEE
Hwang Suk KIM
Hongsoo LEE
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Industry Collaboration Foundation of Ewha University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages

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  • the present disclosure relates to a pharmaceutical composition for suppressing cancer metastasis containing a novel Nm23 activator.
  • Cancer metastasis is one of the most important factors determining the prognosis of cancer patients and is the main process that determines death caused by cancer.
  • cancer therapies such as surgery, radiotherapy, chemotherapy and the like, a lot of efforts have been made to improve the survival of patients, but efforts have still been made to improve the survival of cancer patients.
  • the field of studying cancer metastasis is one of the last strategies to overcome cancer, and studies on cancer metastasis suppressors are essential for developing metastasis-suppressing drugs.
  • Nm23 is a gene encoding a protein involved in the development and differentiation of normal tissue, and the expression of Nm23 has been reported to decrease in various metastatic cell lines.
  • Nm23 protein consisting of 150 to 180 amino acids comprises a leucine zipper motif and has a dinucleotide phosphate kinase (NDPK) activity.
  • NDPK dinucleotide phosphate kinase
  • Nm23-H1 has been shown to play an important role in cancer metastasis and various other cellular mechanisms, for example, proliferation, embryonic development, differentiation, tumor formation, and the like.
  • FIG. 1 is a view showing the stages of cancer metastasis.
  • the metastasis of cancer occurs through a series of sequential stages in which cancer cells in the primary tumor invade blood vessels, travel through the blood vessels, survive and form new colonies at secondary sites.
  • Nm23-H1 is involved in cancer metastasis suppressing activity at various stage of the cancer metastasis process, such as invasion/intravasation, extravasation, metastatic colonization, etc. (Horak C E, et al., The role of metastasis suppressor genes in metastatic dormancy, APMIS. (2008) July-August; 116(7-8):586-601).
  • Nm23 is a nucleotide diphosphate kinase (NDPK) protein, an enzyme that converts NDP (UDP, GDP, CDP) into NTP (UTP, GTP, CTP) using ATP and regulates the intracellular level of NTP.
  • NDPK nucleotide diphosphate kinase
  • FIG. 2 is a schematic diagram showing the NDPK activity of Nm23.
  • Nm23-H1 has been found to be closely associated with decreased cancer cell invasion (Lee E, et al., Multiple functions of Nm23-H1 are regulated by oxido-reduction system, PLoS One. (2009) Nov. 23; 4(11):e7949).
  • the present inventors have conducted research and development on a small molecule substance that modulates the activity of Nm23 involved in the cancer metastasis process, thereby completing the present disclosure.
  • a pharmaceutical composition of the present disclosure which contains, as an active ingredient, a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, acts as an activator of Nm23-H1 and/or Nm23-H2 and suppresses the metastasis and invasion of cancer cells. Therefore, the Nm23 activator according to the present disclosure can be very useful as a pharmaceutical composition for suppressing metastasis of cancer.
  • FIG. 1 is a schematic view showing cancer metastasis stages.
  • FIG. 2 is a schematic view showing the NDPK activity of Nm23.
  • FIG. 3 panels A-E show the results of analyzing NDPK activity for a compound of Formula 2-1.
  • FIG. 4 shows the results of performing isothermal titration calorimetry on a compound of Formula 2-1.
  • FIG. 5 panels A-B show the results of plasmon resonance analysis.
  • FIG. 6 panels A-E show the results obtained by treating two types of breast cancer cell lines with a compound of Formula 2-1, observing the morphological changes of the cells and observing Rac1 activity in each of the cell lines.
  • FIG. 7 panels A-D show the results of verifying the invasion and migration inhibitory activity of a compound of Formula 2-1 on MDA-MB-231 cells.
  • FIG. 8 shows the metastasis suppressing activity of a compound of Formula 2-1 in a breast cancer metastasis model.
  • FIG. 9 panels A-B show the changes in tumor volume and mouse body weight by treatment with a compound of Formula 2-1.
  • FIG. 10 shows the metastasis suppressing activity of a compound of Formula 2-1 in a breast cancer metastasis model.
  • the present inventors have identified compounds that increase the NDPK activity of Nm23, thereby completing the present disclosure.
  • One aspect of the present disclosure is directed to a pharmaceutical composition for suppressing cancer metastasis containing, as an active ingredient, a compound represented by the following Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • ring A is cyclohexene, cyclohexane or benzene.
  • the compound represented by Formula 1 is a compound represented by any one of the following Formulas 2 to 4:
  • the stereoisomer may exist as an optical isomer, a racemate, a racemic mixture, a single enantiomer, a diastereomeric mixture, or each diastereomer.
  • This isomer can be separated by a conventional technique, for example, resolution using column chromatography or HPLC.
  • the stereoisomer of the compound represented by Formula 1 may be stereospecifically synthesized using optically pure starting materials and/or reagents whose configurations are known.
  • the stereoisomer of the compound represented by Formula 1 has an E form.
  • the compound represented by Formula 1 may be any one of the following Formulas 2-1 to 4-1:
  • the compounds of Formulas 2-1 to 4-1 may be produced, for example, by the process described in Preparation Examples 1 to 3 of the present disclosure, but are not limited thereto.
  • the pharmaceutically acceptable salt refers to salts which are commonly used in the pharmaceutical field, and examples thereof include inorganic ion salts formed with calcium, potassium, sodium, magnesium, etc.; inorganic acid salts formed with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc.; organic acid salts formed with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonic acid salts formed with methanesulfonic acid, ethanesulfonic acid,
  • the pharmaceutical composition of the present disclosure may act as an activator of Nm23-H1, an activator of Nm23-H2 or an activator of Nm23-H1 and Nm23-H2.
  • the compound of Formula 1 according to the present disclosure may form a hydrophobic pocket by interaction with Nm23-H1, thus controlling the exposure of the active site and the kpn-loop known to play the most important role in the regulation of NDPK activity and allosterically increasing NDPK activity.
  • the compound of Formula 1 according to the present disclosure may also exhibit the same activity on Nm23-H2 which is another subtype of Nm23 ( FIG. 3 and Table 2).
  • the compound represented by Formula 1 according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may further promote the activity of Nm23 in the presence of ATP ( FIG. 4 ).
  • the cancer may be any one selected from the group consisting of breast cancer, lung cancer, melanoma, prostate cancer, colorectal cancer, bladder cancer, bone cancer, blood cancer, thyroid cancer, parathyroid cancer, bone marrow cancer, rectal cancer, throat cancer, laryngeal cancer, esophageal cancer, pancreatic cancer, gastric cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, head or neck cancer, gallbladder cancer, oral cancer, colon cancer, anal cancer, central nervous system tumor, liver cancer, and colorectal cancer.
  • the pharmaceutical composition of the present disclosure may further contain components, which do not increase the effect of the composition but may be commonly used in pharmaceutical compositions to improve the smell, taste, visual aspect and the like of the compositions.
  • the pharmaceutical composition of the present disclosure may further contain pharmaceutically acceptable additives.
  • the pharmaceutically acceptable additives include, for example, but are not limited to, starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, milk sugar, mannitol, malt, gum Arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba lead, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, white sugar, dextrose, sorbitol and talc.
  • the pharmaceutical composition may further contain one or more active ingredients exhibiting the same or similar medicinal effect, in addition to the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present disclosure may contain pharmaceutically acceptable carriers and may be formulated for oral or parenteral administration and for human or veterinary use.
  • the pharmaceutical composition of the present disclosure may be formulated using diluents or excipients, including fillers, extenders, binders, wetting agents, disintegrants and surfactants.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid formulations may be prepared by mixing the pharmaceutical composition containing the compound of the present disclosure with at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin or the like.
  • lubricants may be used, such as magnesium stearate and talc.
  • Liquid formulation for oral administration include suspensions, liquid solutions, emulsions and syrups, and may include various excipients, for example, wetting agents, sweeteners, flavoring agents and preservatives, in addition to water and liquid paraffin, which are frequently used simple diluents.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • non-aqueous solvents or suspending agents there may be used propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like.
  • As the base of the suppositories there may be used witepsol, Macrogol, Tween 61, cacao butter, laurin fat, glycerogelatin, and the like.
  • the pharmaceutical composition of the present disclosure may be administered orally or parenterally according to a desired method.
  • the pharmaceutical composition may be applied externally to the skin or administered by intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection, but is not limited thereto.
  • composition of the present disclosure may be used alone, but may also be used in combination with various cancer treatment methods, such as radiotherapy, chemotherapy, etc., in order to increase the efficiency of treatment.
  • An another aspect of the present disclosure is directed to a method for suppressing cancer metastasis comprising a therapeutically effective amount of a composition containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a still another aspect of the present disclosure is directed to the use of the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for suppressing cancer metastasis.
  • the pharmaceutical composition of the present disclosure may be administered to a subject to suppress cancer metastasis.
  • subject refers to mammals such as horses, sheep, pigs, goats, etc., including humans who have a cancer or a disease caused directly or indirectly thereby and in whom symptoms of the disease may be improved by administering the pharmaceutical composition of the present disclosure, but is not limited thereto.
  • administering means introducing the pharmaceutical composition of the present disclosure to a subject by any suitable method.
  • the pharmaceutical composition of the present disclosure may be administered orally or parenterally via any route as long as it may reach a target tissue.
  • the pharmaceutical composition of the present disclosure may be administered by any device that allows the pharmaceutical composition to migrate to target cells.
  • the pharmaceutical composition of the present disclosure may be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount refers to an amount sufficient to treat diseases, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the effective dose level of the pharmaceutical composition may be determined depending on factors, including the patient's body weight, sex, age, health conditions, the severity of the disease, the activity of the drug, sensitivity to the drug, the duration of administration, the route of administration, excretion rate, the duration of treatment, drugs used in combination with the composition, and other factors well known in the medical field.
  • the pharmaceutical composition of the present disclosure may be administered individually or in combination with other therapeutic agents. For co-administration, the pharmaceutical composition may be administered sequentially or simultaneously with conventional therapeutic agents.
  • the pharmaceutical composition may be administered in a single or multiple dosage form. It is important to administer the pharmaceutical composition in the minimum amount that can exhibit the maximum effect without causing side effects, in view of all the above-described factors, and this amount can be easily determined by a person skilled in the art.
  • the pharmaceutical composition may be administered once or several times a day. However, the above-described dose and administration mode are not intended to limit the scope of the present disclosure.
  • nBuLi (2.48 M in hexane) (1.95 equivalents) was added to a solution of diethyl 3,4-dimethoxybenzyl phosphonate (2.0 equivalents) in tetrahydrofuran at 0° C.
  • the mixture was stirred at mom temperature for 30 minutes, and then the temperature was lowered again to 0° C., and a solution of (1S,2S)-2-(3,4-dimethoxyphenyl)cyclohex-3-enecarbaldehyde (1.0 equivalent) and DMPU (5.0 equivalents) in THF was added to the mixture through a cannula.
  • the mixture was stirred overnight at mom temperature, and then the reaction was terminated by adding ammonium chloride and water.
  • the reaction mixture was extracted with ethyl acetate, dried with MgSO 4 , and then concentrated and separated on silica gel by column chromatography.
  • the compound of Formula 2-1 may also be produced according to the following Reaction Formula 5:
  • o-bromobenzaldehyde (1.0 equivalent) was dissolved in DMF, and then 3,4-dimethoxyphenylboronic acid (1.0 equivalent), 2M Na 2 CO 3 (3.0 equivalents) and Pd(PPh 3 ) 4 (0.01 equivalents) were added thereto at mom temperature.
  • the mixture was stirred overnight at 80° C. and diluted with ethyl acetate, and then the reaction was terminated by adding ammonium chloride and water. Thereafter, the mixture was extracted with ethyl acetate, and the organic layer was dried with MgSO 4 . The mixture was filtered, and the collected organic layer was concentrated, and then separated on silica gel by column chromatography.
  • the compound d of Formula 3-1 was synthesized in the same manner as process D of Preparation Example 1 above.
  • the results of 1 H NMR of the produced compound of Formula 3-1 are as follows.
  • NDPK assay buffer 20 mM HEPES, 3 mM MgCl 2
  • NDPK assay buffer 20 mM HEPES, 3 mM MgCl 2
  • a cell lysate obtained from 5,000K MDA-MB-231 cells lysed with a protease inhibitor cocktail and an NDPK assay buffer was centrifuged at 8,000 rpm for 10 minutes at 4° C. 40 ⁇ L of the lysate was incubated with the test substance for 5 minutes, and then 50 ⁇ M UDP was added thereto and reacted with NDPK.
  • ATP consumption was assessed by an ATP determination kit (Molecular probe, USA).
  • ITC experiment was performed using the ITC200 system (Malvern Inc.), and the data were analyzed using ORIGIN 7.0 program.
  • the concentration of Nm23-H1 protein in the cells was 30 ⁇ M, and the syringe contained 300 ⁇ M of the activator or 1 mM ATP.
  • the activator was prepared at a concentration of 50 mM in DMSO (dimethyl sulfoxide) and stored at ⁇ 20° C.
  • ITC buffer contained (pH 7.5) 150 mM NaCl, 3 mM MgCl 2 and 20 mM HEPES in up to 2% DMSO. For titration, each 2 ⁇ L was injected 20 times 25° C. at intervals of 150 seconds.
  • the experimental raw data were corrected by subtracting the value for the buffer, and then fitted to a single site binding model.
  • the titration data were fitted using a nonlinear least squares curve-fitting algorithm with three floating variables: stoichiometry (N), dissociation constant (KD), and change of enthalpy of interaction.
  • Nm23-H1 (1 mg/ml) in 10 mM S.A buffer (pH 4.5) was immobilized using the standard amino coupling at 20 ⁇ L/min for 10 minutes on a carboxymethyl dextran hydrogel (CMDH) surface sensor chip (Reichert Technologies, NY) until saturation was achieved.
  • CMDH carboxymethyl dextran hydrogel
  • the sensor surface was regenerated after each association and dissociation cycle by injecting 2M NaCl for 1 min. Sensorgrams were fitted to a simple 1:1 Langmuir interaction model (A+B ⁇ AB) using data analysis program Scrubber 2.0 (BioLogic Sofware, Australia, and Kaleida Graph Sofware, Australia).
  • K D is a value obtained by calculating K d /K a .
  • FIG. 3 shows the results of analyzing the activity of NDPK for the compound of Formula 2-1.
  • the compound of Formula 2-1 in each figure was indicated as NMac1.
  • the compound of Formula 2-1 according to the present disclosure showed the same activity not only for Nm23-H1, but also for Nm23-H2 which is another subtype of Nm23. More specifically, it can be confirmed through FIG. 3E that the compound of Formula 2-1 according to the present disclosure specifically activates only Nm23-H1 which is the active form of Nm23-H1.
  • FIG. 4 shows the results of performing isothermal titration calorimetry for the compound of Formula 2-1. From the results in FIG. 4 , it could be confirmed that the direct interaction between Nm23-H1 and the compound of Formula 2-1 according to the present disclosure occurred and was further enhanced in the presence of ATP.
  • FIG. 5 shows the results of plasmon resonance analysis. From the results in FIG. 5 , it could be confirmed that the compound of the present disclosure did bind directly to Nm23-H1.
  • MDA-MB-231 cells were grown in a 100 mm dish and treated with the compound of Formula 2-1 or 0.05% DMSO at an indicated concentration for 16 hours. Active Rac1 pulldown assays were performed according to the manufacturer's instructions (Termo Fisher Scientifc).
  • MDA-MB-231 cells were grown on the SecureslipTM (Sigma) cell culture glass cover slip to a confluence of 50 to 70%, and incubated in the presence or absence of the compound of Formula 2-1 for various periods of time.
  • the cells were gently washed with cold HBSS, and then fixed with 4% paraformaldehyde-containing HBSS in RBS for 10 minutes. After washing with HBSS, permeabilization with 0.1% Triton X-100 was performed for 10 minutes at mom temperature. After washing twice with HBSS, the cells were blocked with HBSS containing 3% BSA, 0.2% Tween 20 and 0.2% gelatin at room temperature for 1 hour, and incubated with primary antibody at mom temperature for 1 hour. Then, the cells were incubated with fluorochrome-conjugated species-specific secondary antibodies for 1 hour.
  • All the antibodies were diluted with 1% BSA-containing HBSS. Coverslips were mounted with anti-fading solution, and viewed using a ⁇ 63 objective lens of an LSM510 META (Zeiss) laser scanning confocal microscope.
  • the cells When cells reached a confluence of 70%, the cells were treated with the compound of Formula 2-1 for 16 hours. 1 ⁇ 10 5 cells were suspended in PBS-free medium and added onto a Boyden chamber membrane. 10% PBS-containing culture was added to the bottom of the membrane. The chamber was incubated at 37° C. under 5% CO 2 for 4 hours. The migrated cells were fixed and stained with crystal violet/methanol. The cells were photographed, and the migrated cells were counted and normalized to control cells.
  • FIG. 6 shows the results obtained by two types of breast cancer cell lines with the compound of Formula 2-1, observing the morphological changes of the cells and observing the Rac1 activity in each of the cell lines.
  • FIG. 6A shows the confocal microscopic observation of the cells treated with the compound of Formula 2-1. Looking at the change of F-actin in the MDA-MB-231 cells, it can be confirmed that ruffles decreased and intercellular contact increased. This implies that Nm23-H1 inhibits the activity of Rac1 involved in cell migration and reduces cell migration.
  • FIG. 6B shows the results of measuring changes in morphology and Rac1 activity by treatment with the compound of Formula 2-1 in MDA-MB-231 cells which are a triple negative breast cancer cell line.
  • a pull-down assay of activated Rac1 was conducted, the component of Formula 2-1 according to the present disclosure reduced the activity of Rac1 in a concentration-dependent manner.
  • FIGS. 6C and 6D it can be confirmed that the effect of the compound of Formula 2-1 was abolished by knockdown of Nm23-H1. This suggests that inhibition of Rac1 activity occurs through Nm23-H1.
  • FIG. 7 shows the results of verifying the invasion and migration inhibitory activity of the compound of Formula 2-1 on MDA-MB-231 cells.
  • FIG. 7A shows the results of performing invasion assay and transwell migration assay in MDA-MB-231 cells which are a triple negative breast cancer cell line.
  • FIG. 7B shows the Nm23-H1 activity of the compound of Formula 2-1 on A549 cells which are a lung cancer cell line. From the results in FIG. 7B , it can be seen that the compound of Formula 2-1 reduced both the transwell migration and matrigel invasion of A549 cells.
  • FIG. 7C shows the Nm23-H1 and Nm23-H2 activities of the compound of Formula 2-1.
  • the effect of the compound of Formula 2-1 was reduced by knockdown of Nm23-H1 and Nm23-H2. This suggests that the in vitro metastasis suppressing activity of the compound of Formula 2-1 occurs through Nm23-H1 and Nm23-H2.
  • MDA-MB-231 luc cells were applied to a breast cancer metastasis model.
  • MDA-MB-231 cells were injected into the mammary fat pad of nude mice, and then when the tumor size reached 100 mm, the compound of Formula 2-1 was injected daily at a dose of 10 mg/kg, and the metastasis of the cells to the lung was observed for 4 weeks.
  • FIG. 8 shows the metastasis suppressing activity of the compound of Formula 2-1 in the breast cancer metastasis model. From the results in FIG. 8 , it can be seen that metastasis of the cells to the lung decreased in the group treated with the compound of Formula 2-1 according to the present disclosure.
  • FIG. 9 shows the changes in tumor volume and body weight by treatment with the compound of Formula 2-1. From the results in FIG. 9 , it could be confirmed that the volume of the tumor decreased in the group treated with the compound of Formula 2-1 according to the present disclosure.
  • FIG. 10 shows the metastasis suppressing activity of the compound of Formula 2-1 in the breast cancer metastasis model. From the results in FIG. 10 , it could be confirmed that the cells that metastasized to the lung statistically significantly decreased.
  • the compound represented by Formula 1 according to the present disclosure may be used as a pharmaceutical composition which is effective for suppressing cancer metastasis by increasing the NDPK activity of Nm23.

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KR1020180049329A KR102034958B1 (ko) 2017-04-28 2018-04-27 Nm23 활성제를 포함하는 암 전이 억제용 약학적 조성물
PCT/KR2018/005036 WO2018199727A1 (ko) 2017-04-28 2018-04-30 Nm23 활성제를 포함하는 암 전이 억제용 약학적 조성물

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KR102442998B1 (ko) * 2019-12-20 2022-09-14 주식회사 하임네이처 NDPK 활성제 및 H-prune 억제제를 포함하는 암의 예방 또는 치료용 약학 조성물
CN114404570B (zh) * 2022-01-20 2023-05-30 中国药科大学 一种新型抗肿瘤转移多肽及其应用

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